Extended release methazolamide formulation

ABSTRACT

A once-a-day controlled release oral dosage form of methazolamide is provided. The dosage form comprises a therapeutically effective amount of methazolamide and a high molecular weight binder. The dosage is configured for once-daily administration to a subject in need thereof, and releases methazolamide over a period of about twenty-four hours.

CROSS REFERENCES TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.15/972,943, now U.S. Pat. No. 10,493,063, issued Dec. 3, 2019, which isa continuation of U.S. application Ser. No. 15/621,298, now U.S. Pat.No. 9,980,946, issued May 29, 2018, which claims priority to U.S.Provisional Application No. 62/450,233, filed Jan. 25, 2017, the entirecontents of which is incorporated by reference herewith.

FIELD OF INVENTION

The present disclosure generally relates to an extended releaseformulation of methazolamide. More specifically, it relates to an oraldosage form of methazolamide which provides a release profile suitablefor once daily dosing while exhibiting good bioavailability.

BACKGROUND OF THE INVENTION

Ocular conditions characterized by elevated intraocular pressure, suchas chronic open-angle glaucoma or secondary glaucoma, have beensuccessfully treated by administration of methazolamide, and analogs,derivatives, and prodrugs thereof. Methazolamide is a carbonic anhydraseinhibitor that slows the formation of excess fluids behind the cornea byinhibiting a chemical reaction at the ciliary body.

Methazolamide is commercially available as an oral dose in 25 and 50 mgimmediate release tablets, and is typically taken by a patient two tothree times daily (50-150 mg/day). While effective, the high dosingfrequency a patient must follow in order to attain effective therapyusing the commercially available immediate release tablets reducespatient compliance because patients often miss doses as a result ofpatient forgetfulness or the inconvenience of having to take multipledoses throughout the day. Therefore, it is desirable to have an extendedrelease methazolamide formulation that provides a longer period ofpharmacological action after administration than is ordinarily obtainedafter administration of immediate-release dosage forms.

Many techniques have been used to provide controlled andextended-release pharmaceutical dosage forms in order to maintaintherapeutic serum levels of medicaments. However, in the case ofrelatively water insoluble drugs such as methazolamide, developing asustained release formulation generally requires considerableexperimentation because it is often not possible to readily predictwhether a particular extended release formulation will yield the desiredsustained release profile while also maintaining suitable handlingproperties such as sufficient tablet hardness and appropriatefriability.

Owing to the fact that water insoluble drugs tend to yield inconsistentdrug release profiles, the task of preparing controlled releaseformulations of methazolamide has proven difficult. There is nocommercially available extended release methazolamide formulation on themarket.

U.S. Pat. No. 6,214,381 describes an extended-release methazolamideformulation that releases methazolamide over a period of 12 hours orless. However, this formulation is inadequate for once daily dosingbecause the methazolamide release profile is not optimal and does notprovide sufficient coverage over a 24 hour period. Further, thisformulation cannot be readily used in a 24 hour extended-releasemethazolamide formulation because attempts to extend the drug releaseprofile from 12 hours to 24 hours using this formulation results in acomposition which has inadequate handing properties (e.g.compressibility and friability issues), thereby precluding thecomposition's use as an orally administrable once-a-day dose.

Therefore, what are needed are extended release formulations ofmethazolamide that can deliver methazolamide over 24 hours with asuitable drug release profile when given to a subject, thus allowingonce daily oral administration.

SUMMARY OF THE INVENTION

This disclosure generally provides extended release formulations ofmethazolamide that can deliver methazolamide over 24 hours. Theformulations exhibit sustained-release properties adequate to providetherapeutic effectiveness when administered orally not more than oncedaily to a subject in need thereof.

According to one aspect of the present disclosure, there is provided aonce-a-day controlled release oral dosage form including a drug selectedfrom methazolamide, a methazolamide analog, a methazolamide derivative,a methazolamide prodrug, or a combination thereof; and a high molecularweight binder, wherein the dosage form provides an in vitro release offrom about 50% to about 80% by weight of the drug at 12 hours whenmeasured by the USP Paddle Method at 100 rpm in acetate buffer (pH=4.5),and wherein the dosage form provides an in vitro release of about 90% orgreater by weight of the drug at 24 hours when measured by the USPPaddle Method at 100 rpm in acetate buffer (pH=4.5).

According to another aspect of the present disclosure, there is provideda method for treating an ocular condition characterized by elevatedintraocular pressure including administering to a patient in needthereof a once-a-day controlled release oral dosage form ofmethazolamide.

BRIEF DESCRIPTION OF THE DRAWINGS

Referring now to the drawings, which are meant to be exemplary and notlimiting, and wherein like elements are numbered alike. The detaileddescription is set forth with reference to the accompanying drawingsillustrating examples of the disclosure, in which use of the samereference numerals indicates similar or identical items. Certainembodiments of the present disclosure may include elements, components,and/or configurations other than those illustrated in the drawings, andsome of the elements, components, and/or configurations illustrated inthe drawings may not be present in certain embodiments.

FIG. 1 shows a drug release profile of one embodiment of apharmaceutical composition.

FIG. 2 shows a drug release profile of one embodiment of apharmaceutical composition.

DETAILED DESCRIPTION OF THE INVENTION

After rigorous investigation, the inventors surprisingly found itpossible to produce an extended release oral dose formulation ofmethazolamide for once daily administration that releases methazolamideover a period of twenty-four hours. More particularly, the inventorssurprisingly discovered that a composition formed from a unique range ofmethazolamide particle sizes not present in prior formulations, incombination with an increase in excipient viscosity and/or excipientpercentage in the composition relative to prior formulations, resultedin a methazolamide composition that releases methazolamide over atwenty-four hour period, thereby providing a composition suitable foruse in a once-a-day dosing regimen.

It is understood that aspects and embodiments of the invention describedherein include “consisting” and/or “consisting essentially of” aspectsand embodiments.

As used herein, “about” refers to within 10% of a stated value. Forexample, about 50 encompasses 45 to 55, inclusive. When the term “about”modifies a numerical range, the term applies to both ends of the range(e.g. about 5 to 10 means about 5 to about 10).

Throughout this disclosure, various aspects of the invention arepresented in a range format. It should be understood that thedescription in range format is merely for convenience and brevity andshould not be construed as an inflexible limitation on the scope of theinvention. Accordingly, the description of a range should be consideredto have specifically disclosed all the possible sub-ranges as well asindividual numerical values within that range. For example, descriptionof a range such as from 1 to 6 should be considered to have specificallydisclosed sub-ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numberswithin that range, for example, 1, 2, 3, 4, 5, and 6. This appliesregardless of the breadth of the range.

As used herein, “subject” or “patient” refers to an animal, a non-humanmammal or a human. As used herein, “animals” include a pet, a farmanimal, an economic animal, a sport animal and an experimental animal,such as a cat, a dog, a horse, a cow, an ox, a pig, a donkey, a sheep, alamb, a goat, a mouse, a rabbit, a chicken, a duck, a goose, a primate,including a monkey and a chimpanzee.

Formulations

The present disclosure provides an extended release oral dose ofmethazolamide that exhibits sustained-release properties adequate toprovide therapeutic effectiveness when administered orally not more thanonce daily to a subject in need thereof. The extended release doses areformulated to provide a sustained rate of methazolamide drug release invivo over twenty-four hours. The pharmaceutical compositions generallycomprise methazolamide and a high molecular weight binder. Thecompositions can also include fillers, lubricants, and/or flow agents.Tablets are the preferred oral dosage form for the methazolamidecompositions of the present disclosure; however, this disclosurecontemplates that the compositions may also be formulated as hard gelcapsules, soft gel capsules, and the like.

The active ingredient in the pharmaceutical formulations describedherein is methazolamide, a methazolamide analog, a methazolamideprodrug, and/or a methazolamide derivative. Methazolamide, a sulfonamidederivative, is a white crystalline powder, weakly acidic, and slightlysoluble in water, alcohol and acetone. The chemical name formethazolamide is:N-[5-(aminosulfonyl)-3-methyl-1,3,4-thiadiazol-2(3H)-ylidene]acetamide.As used herein, methazolamide, methazolamide analogs, methazolamideprodrugs, and methazolamide derivatives also include salts thereof.Examples of pharmaceutically acceptable salts include sulfates,pyrosulfates, bisulfates, sulfites, bisulfites, phosphates,monohydrogen-phosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates, propionates,decanoates, caprylates, acrylates, formates, isobutyrates, caproates,heptanoates, propiolates, oxalates, malonates, succinates, suberates,sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates,benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates,hydroxybenzoates, methoxybenzoates, phthalates, sulfonates,methylsulfonates, propylsulfonates, besylates, xylenesulfonates,naphthalene-1-sulfonates, naphthalene-2-sulfonates, phenylacetates,phenylpropionates, phenylbutyrates, citrates, lactates,γ-hydroxybutyrates, glycolates, tartrates, and mandelates. The activeingredient can be obtained from any suitable source.

Exemplary methazolamide analogs include acetazolamide,hydroxymethazolamide,6-[β-glucopyranosyl)oxyethoxy]-2-benzothiazolesulfonamide,N-[5-(aminosulfonyl)-3-methyl-1,3,4-thiadiazol-2(3H)-ylidene]-2-[glycolylhydroxy]acetamide,N-[5-(aminosulfonyl)-3-methyl-1,3,4-thiadiazol-2(3H)-ylidene]-2-hydroxypropanamide,N-[5-(aminosulfonyl)-3-methyl-1,3,4-thiadiazol-2-(3H)-ylidene]-2-D-glucuronamide,2-benzyloxcarbonylimino-3-methyl-delta⁴-1,3,4-thiadiazoline-5-sulfonamide,2-[4-pyridylmethyloxy-carbony]imino-3-methyl-delta⁴-1,3,4-thiadiazoline-5-sulfonamide,2-[4-hydroxymethylbenzyloxycarbonyl]imino-3-methyl-delta⁴-1,3,4-thiadiazoline-5sulfonamide],2-[4-hydroxymethylphenylacetyl]-imino-3-methyl-delta⁴-1,3,4-thiadiazoline-5-sulfonamide,2-ethoxycarbonylimino-3-methyl-delta⁴-1,3,4-thiadiazoline-5-sulfonamide,2-[4-pyridylmethyloxycarbony]imino-3-methyl-delta⁴-1,3,4-thiadiazoline-5-sulfonamide,2-[4-hydroxymethylbenzyloxycarbonyl]imino-3-methyl-delta⁴-1,3,4-thiadiazoline-5-sulfonamide,and2-[4-hydroxymethylphenylacetyl]imino-3-methyl-delta₄-1,3,4-thiadiazoline-5-sulfonamide.Additional methazolamide analogs can be found, for example, in U.S. Pat.Nos. 5,157,044 and 5,104,887, the contents of which are incorporatedherein in their entirety.

Exemplary methazolamide prodrugs can include hydroxymethazolamides ofthe formula:

wherein “Z” represents a water soluble carrier (e.g. monosaccharidessuch as D- and L-glucose, 6-carboxylic acid derivatives ofmonosaccharides such as D- and L-glucuronic acid, and D- and L-gluconicacid, and the like) and “A” is a moiety which is attached to thecarbonic anhydrase inhibitor which allows it to still retain carbonicanhydrase inhibitory activity, but also form an enzymatically cleavablebond between A and Z (e.g. a C₁ to C₅ alkyl such as a hydroxyethoxy,hydroxy, hydroxyacetamido, and amino). Additional details regardingexemplary methazolamide prodrugs can be found, for example, in U.S. Pat.No. 5,095,026, the contents of which are incorporated herein in theirentirety.

Exemplary methazolamide derivatives can includeN-[5-(aminosulfonyl)-3-methyl-1,3,4-thiadiazol-2(3H)-ylidene]-2-acetyloxyacetamide.Additional details regarding exemplary methazolamide derivatives can befound, for example, in U.S. Pat. No. 5,225,424, the contents of whichare incorporated herein in their entirety.

The pharmaceutical compositions described herein can comprise about 50mg to 500 mg of methazolamide per dose. In preferred embodiments, thepharmaceutical compositions comprise about 50 mg to 300 mg ofmethazolamide per dose. Thus, in preferred embodiments, a pharmaceuticalcomposition can comprise, for example, about 50, 75, 100, 125, 150, 175,200, 225, 250, 275, or 300 mg of methazolamide per dose. The exactamount of methazolamide is preferably selected such that thepharmaceutical compositions provide a single, once-a-day,therapeutically effective dose of methazolamide. By once-a-day dose ofmethazolamide, it is meant that the pharmaceutical composition releasesmethazolamide over an approximately 24 hour period such that anindividual need only take a single dose per day.

The methazolamide particles in the pharmaceutical compositions can haveany suitable size distribution. In some embodiments, the methazolamideparticles have the following size distribution: a D(v, 0.5) of about 1μm to 300 μm. In some embodiments, the methazolamide particles have thefollowing size distribution: a D(v, 0.1) of about 1 μm to 100 m, and aD(v, 0.9) of about 200 μm to 300 μm. In some embodiments, themethazolamide particles have the following size distribution: a D(v,0.1) of about 1 μm to 100 μm, a D(v, 0.5) of about 100 μm to 200 μm, anda D(v, 0.9) of about 200 μm to 300 μm. In some embodiments, themethazolamide particles have the following size distribution: a D(v,0.1) of about 30 μm to 60 μm, a D(v, 0.5) of about 100 μm to 150 μm, anda D(v, 0.9) of about 240 μm to 290 μm. In some embodiments, themethazolamide particles have the following size distribution: a D(v,0.1) of about 35 μm to 55 μm, a D(v, 0.5) of about 115 μm to 140 μm, anda D(v, 0.9) of about 250 μm to 275 μm.

The following conventions apply when describing particle sizedistribution. D(v, 0.1) means that 10% of the particles are smaller thanthis diameter. D(v, 0.5) is the median particle diameter. D(v, 0.9)means that 90% of the particles are smaller than this diameter.

The pharmaceutical compositions described herein can comprise a highmolecular weight binder, which can control the release of methazolamidefrom the pharmaceutical composition. Low molecular weight binders havelower viscosities which result in faster drug release from the tabletand quicker drug release profiles. Suitable high molecular weightbinders include, but are not limited to, hydroxypropyl methylcellulose,ethylcellulose, methylcellulose, sodium carboxymethylcellulose,hydroxypropyl cellulose, microcrystalline cellulose, starch,polyvinylpyrrolidone, sodium alginate, xantham gum and polyethyleneglycols.

In a preferred embodiment, the high molecular weight binder ishydroxypropyl methylcellulose (HPMC) having a number average weightequal to or greater than about 80,000 daltons, and more preferably100,000 daltons. Preferably, the hydroxypropyl methylcellulose has amethoxyl content of about 19-24%, a hydroxypropyl content of about7-12%, and an apparent viscosity of about 80,000-120,000 cps in a 2%solution of water at about 20° C. In one embodiment, the HPMC isMETHOCEL™ K 100M Premium CR (available from Dow Chemical Company).METHOCEL™ K 100M Premium CR is a hydroxypropyl methylcellulose which hasa methoxyl content of about 19-24%, a hydroxypropyl content of about7-12%, and an apparent viscosity of about 100,000 cps in a 2% solutionof water at about 20° C.

In some embodiments, fillers can be added as a diluent to achieve theappropriate total tablet weight and hardness. Fillers useful in thepresent disclosure include, but are not limited to, lactose,microcrystalline cellulose, dextrose, calcium phosphate, calciumsulfate, sucrose, mannitol, and starch. In one preferred embodiment, thepharmaceutical compositions include the filler lactose.

In some embodiments, lubricants can be added to reduce friction, preventtablet binding, and aid in the flow of mixture during the tabletingprocess. Lubricants useful in the present disclosure include, but arenot limited to, magnesium stearate, calcium stearate, zinc stearate,polyethylene glycol, sodium benzoate, sodium acetate, stearic acid,talc, hydrogenated vegetable oils, and starch. In one preferredembodiment, the pharmaceutical compositions include the lubricantmagnesium stearate.

In some embodiments, flow agents can be added to maximize the efficiencyof the manufacturing process by facilitating the flow of the particlesthrough the tablet-forming equipment. Flow agents useful in the presentdisclosure include, but are not limited to, lactose, talc, silicondioxide, polyethylene glycol, microcrystalline cellulose, sodiumphosphate and calcium phosphate.

In some embodiments, the pharmaceutical compositions described hereincomprise from about 10 to about 80 percent by weight methazolamide; fromabout 1 to about 60 percent by weight high molecular weight binder; fromabout 0 to about 5 percent by weight of lubricant; and from about 10 toabout 90 percent by weight filler and/or flow agent. More preferably,the pharmaceutical compositions contain from about 30 to about 50percent by weight methazolamide, from about 10 to about 20 percent byweight high molecular weight binder, from about 0 to about 2 percent byweight lubricant, and from about 28 to about 60 percent by weightfillers and/or flow agents. In one particular embodiment, thepharmaceutical composition comprises about 40 percent by weightmethazolamide; about 15 percent by weight hydroxypropyl methylcellulose;from about 0 to about 2 percent by weight magnesium stearate; and fromabout 43 to about 45 percent by weight lactose.

These are preferred dose formulations giving desirable drug releaseprofiles. These formulations provide a controlled release ofmethazolamide for about a twenty-four hour period. However, otherformulations have been envisioned, which will also provide a controlledrelease of methazolamide over an extended period of time.

In some embodiments, the pharmaceutical compositions described hereinhave an in vitro drug release profile such that about 50% to about 80%of the methazolamide has been released at 12 hours and about 90-100% ofthe methazolamide has been released at 24 hours. In some embodiments,the pharmaceutical compositions described herein have an in vitro drugrelease profile such that no more than about 15%, about 20%, about 25%,or about 30% of the methazolamide has been released at 1 hour. In someembodiments, the pharmaceutical compositions described herein have an invitro drug release profile such that no more than about 25%, about 30%,about 35%, about 40%, or about 45% of the methazolamide has beenreleased at 3 hours. In some embodiments, the pharmaceuticalcompositions described herein have an in vitro drug release profile suchthat no more than about 40%, about 45%, about 50%, about 55%, or about60% of the methazolamide has been released at 6 hours. In someembodiments, the pharmaceutical compositions described herein have an invitro drug release profile such that no more than about 70%, about 75%,or about 80% of the methazolamide has been released at 12 hours. In someembodiments, the pharmaceutical compositions described herein have an invitro drug release profile such that no more than about 90%, or about95% of the methazolamide has been released at 18 hours. In someembodiments, the pharmaceutical compositions described herein have an invitro drug release profile such that no less than about 80%, about 85%,about 90%, or about 95% of the methazolamide has been released at 24hours.

In some embodiments, the pharmaceutical compositions described hereinhave an in vitro drug release profile such that no less than about 5%,about 10%, or about 15% of the methazolamide has been released at 1hour. In some embodiments, the pharmaceutical compositions describedherein have an in vitro drug release profile such that no less thanabout 10%, about 15%, about 20%, or about 25% of the methazolamide hasbeen released at 3 hours. In some embodiments, the pharmaceuticalcompositions described herein have an in vitro drug release profile suchthat no less than about 20%, about 25%, about 30%, about 35%, or about40% of the methazolamide has been released at 6 hours. In someembodiments, the pharmaceutical compositions described herein have an invitro drug release profile such that no less than about 45%, about 50%,about 55%, about 60%, about 65%, about 70%, or about 75% of themethazolamide has been released at 12 hours. In some embodiments, thepharmaceutical compositions described herein have an in vitro drugrelease profile such that no less than about 70%, about 75%, about 80%,about 85%, or about 90% of the methazolamide has been released at 18hours. In some embodiments, the pharmaceutical compositions describedherein have an in vitro drug release profile such that about 90% toabout 100% of the methazolamide has been released at 24 hours.

Drug release profiles can be determined using the testing procedures setforth below in the example embodiments section. The drug releaseprofiles of the presently disclosed compositions help ensure that themethazolamide will be delivered in a sustained release manner such thata person need only take a single dose once per day in order to relieveintraocular pressure.

Methods of Manufacture

The pharmaceutical compositions of the present disclosure can bemanufactured using any suitable means known to those of ordinary skillin the art. In one example, a sustained release methazolamidepharmaceutical composition is made by first mixing the pre-weighed dryingredients (e.g. methazolamide, high molecular weight binder, fillers,etc.) in a blender and granulating the mixture with purified water usinga high sheer mixer. The wet granules are dried in a fluid bed.Lubricant, if present in the pharmaceutical composition, can be part ofthe pre-weighed dry ingredients that are initially mixed, or it can beadded to the fluid bed. Dried granules are then screened through a #16mesh screen (1.19 mm), and only the retained granules are milled using aFitzmill fitted with a #1B mesh screen at medium speed and knivesforward. The milled composition is then finally blended using a doublecone tumbler/blender and compressed into tablets. The size of thetablets is dependent on the amount of methazolamide in the tablet andthe amount of other compounds used. Preferably, the tablets are between100 and 800 mg each.

The pharmaceutical compositions can be made using other modifications tothe process including, but not limited to, using a wet granulation fluidother than purified water, such as methanol, ethanol, isopropyl alcohol,or methylene chloride.

Methods of Treatment

Methods for treating an ocular condition characterized by elevatedintraocular pressure are provided. In some embodiments, the methods fortreating an ocular condition characterized by elevated intraocularpressure comprise administering once-daily to a subject in need thereofan extended release oral dose formulation of methazolamide as describedherein. In some embodiments, a therapeutically effective amount ofmethazolamide is administered to a subject in need thereof in atherapeutically effective dosing regimen. A therapeutically effectiveamount of methazolamide, and its therapeutically effective dosingregimen, will be appreciated by those of ordinary skill in the art.

As used herein, the term “therapeutically effective amount” refers tothose amounts that, when administered to a particular subject in view ofthe nature and severity of that subject's disease or condition, willhave a desired therapeutic effect, e.g., an amount which will cure,prevent, inhibit, or at least partially arrest or partially prevent atarget disease or condition. A therapeutically effective amount furtherrefers to that amount of the therapeutic agent sufficient to result inamelioration of symptoms, e.g., treatment, healing, prevention oramelioration of the relevant medical condition, or an increase in rateof treatment, healing, prevention or amelioration of such conditions.

In embodiments, methazolamide is administered to treat ocular conditionswhere lowering intraocular pressure is likely to be of therapeuticbenefit, such as chronic open-angle glaucoma, secondary glaucoma, andpreoperatively in acute angle-closure glaucoma where lowering theintraocular pressure is desired before surgery. In embodiments,methazolamide is administered preoperatively, postoperatively, or both,to lower intraocular pressure in a patient. In embodiments, the methodsfor treating an ocular condition characterized by elevated intraocularpressure comprise administering a therapeutically effective extendedrelease oral dose formulation of methazolamide to a patient once-dailyfor 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, or more days, asneeded for intraocular pressure relief. In embodiments, themethazolamide, when administered in accordance with a therapeuticallyeffective dosing regimen, contributes to lowering intraocular pressurein a subject without being toxic (e.g., without significant sideeffects) to the subject.

A dose of methazolamide can be administered alone or in combination withother medical treatments, or other therapeutic agents. When so used,other therapeutic agents can be administered before, concurrently(whether in separate dosage forms or in a combined dosage form), orafter administration of methazolamide.

Example Embodiments

I. Formulations

In one exemplary embodiment, a pharmaceutical composition for treatingan ocular condition is provided. The pharmaceutical composition is acontrolled release tablet containing 100 or 150 mg of methazolamide andhas the following formulation.

Ingredient % (by weight) mg/Tablet mg/Tablet Methazolamide 43.48 100 150HPMC (METHOCEL ™ 15.07 34.67 52 K 100M Premium CR) Lactose 40.93 94.13141.2 Magnesium Stearate 0.52 1.2 1.8 Total 100 230 345

These are preferred dose formulations giving desirable drug releaseprofiles. These formulations provide an approximately consistent releaseof methazolamide for about a twenty-four hour period. However, otherformulations have been envisioned, which will also provide anapproximately consistent release of methazolamide over an extendedperiod of time.

The tablets having the above exemplary formulation can be manufacturedby a wet granulation method. In one example, all ingredients are weighedbased on either the 100 or 150 mg methazolamide formulation. Themethazolamide, HPMC (METHOCEL™ K 100M Premium CR), and lactose are mixedin a blender. The mixed composition is granulated with purified waterusing a high sheer mixer. The wet granules are dried in a fluid bed, andthe lubricant magnesium stearate is added to the fluid bed. The driedgranules are then screened through a #16 mesh screen (1.19 mm), and onlythe retained granules are milled using a Fitzmill fitted with a #1B meshscreen at medium speed and knives forward. The milled composition isthen finally blended using a double cone tumbler/blender and compressedinto tablets.

II. Testing

Methazolamide particle size testing was performed on unmilledmethazolamide particles and methazolamide particles milled in-house andby a third party vendor according to the above milling procedure.Methazolamide particle size testing was conducted using a Mastersizerlaser particle size analyzer from Malvern Instruments or a sonicshifter. The results of the particle size testing for methazolamideparticles milled in-house, as measured by a laser particle sizeanalyzer, are as follows:

Sample D(v, 0.1) D(v, 0.5) D(v, 0.9) 1 42.15 μm 121.45 μm 255.75 μm 247.67 μm 132.34 μm 269.30 μm 3 48.42 μm 128.46 μm 267.26 μm Average 46.1 μm  127.4 μm  264.1 μm

The results of the particle size testing for unmilled methazolamideparticles, methazolamide particles milled in-house, and methazolamideparticles milled by a third party vendor, as measured by a sonicshifter, are as follows:

% Retained Milled API Milled API Sieve # Unmilled API (in-house) (3^(rd)party) 20 (840 μm) 0.09 1.23 5.15 40 (420 μm) 7.95 1.52 6.14 80 (177 μm)75.05 15.27 21.88 100 (149 μm) 8.04 19.54 17.14 140 (105 μm) 6.01 32.9221.90 200 (74 μm) 2.03 13.00 12.29 Fines Collector 0.83 16.51 15.56Density Bulk Density 0.92 g/mL 0.56 g/mL 0.53 g/mL Trapped Density 1.03g/mL 0.99 g/mL 1.00 g/mL

Drug release testing was performed on the exemplary formulationsdescribed above to determine the specific drug release profiles. Themethod was based upon the current U.S. Pharmacopeia (USP) XXIII (TheUnited States Pharmacopeial Convention, Inc., Rockville, Md., 1998)dissolution test procedure for immediate release products. The methodincluded using a USP Paddle Apparatus II at 100 rpm with acetate buffer(pH=4.5) medium with various sampling points. In the method, a tabletwas dropped into the apparatus and the amount of methazolamide dissolvedin the acetate buffer solution was measured over various time periods asmeasured by UV spectrophotometry at λ=280 nm using a HPLC equipped witha UV detector, as is well known in the art. This method gave thefollowing dissolution profiles (e.g. drug release profiles) of thetablets containing 100 mg or 150 mg of methazolamide:

Ingredient 1 hr 3 hrs 6 hrs 12 hrs 18 hrs 24 hrs 100 mg tablet %released 12 22 38 68 87 98 mg equiv. 12 22 38 68 87 98 150 mg tablet %released 12 21 35 61 82 93 mg equiv. 18 31.5 52.5 91.5 123 139.5

The drug release profile showed a release of about 60-80% methazolamideat 12 hours and a >90% release of methazolamide at 24 hours.

The detailed description set forth above is provided to aid thoseskilled in the art in practicing the invention. However, the inventiondescribed and claimed herein is not to be limited in scope by thespecific embodiments described above, as these embodiments are presentedas mere illustrations of several aspects of the invention. Anycombinations and modifications of the described methods and components,and compositions used in the practice of the methods, in addition tothose not specifically described, will become apparent to those skilledin the art based on the present disclosure and do not depart from thespirit or scope of the present invention. Such variations,modifications, and combinations are also encompassed by the presentdisclosure and fall within the scope of the appended claims.

What is claimed is:
 1. A once-a-day controlled release oral dosage formcomprising 50 to 300 mg of methazolamide or a pharmaceuticallyacceptable salt thereof and a high molecular weight binder in acontrolled release oral dosage form that provides in vivo at steadystate over an entire 24 hour period a therapeutically effective amountof the methazolamide or the pharmaceutically acceptable salt thereof totreat an ocular condition in a human characterized by elevatedintraocular pressure, wherein the dosage form provides an in vitrorelease of from about 50% to about 80% by weight of the methazolamide orpharmaceutically acceptable salt thereof at 12 hours when measured bythe USP Paddle Method at 100 rpm in acetate buffer (pH=4.5), wherein thedosage form provides an in vitro release of about 90% or greater byweight of the methazolamide or pharmaceutically acceptable salt thereofat 24 hours when measured by the USP Paddle Method at 100 rpm in acetatebuffer (pH=4.5), and wherein the methazolamide or a pharmaceuticallyacceptable salt thereof has a particle size distribution as follows: aD(v, 0.1) of about 1 μm to 100 μm, a D(v, 0.5) of about 100 μm to 150μm, and a D(v, 0.9) of about 200 μm to 300 μm.
 2. The controlled releaseoral dosage form of claim 1, wherein the controlled release oral dosageform is a tablet.
 3. The controlled release oral dosage form of claim 1,wherein the controlled release oral dosage form comprises about 100 mgof methazolamide or pharmaceutically acceptable salt thereof.
 4. Thecontrolled release oral dosage form of claim 1, wherein the controlledrelease oral dosage form comprises about 150 mg of methazolamide orpharmaceutically acceptable salt thereof.
 5. The controlled release oraldosage form of claim 1, wherein the controlled release oral dosage formcomprises about 175 mg of methazolamide or pharmaceutically acceptablesalt thereof.
 6. The controlled release oral dosage form of claim 5,wherein the high molecular weight binder is hydroxypropylmethylcellulose (HPMC).
 7. The controlled release oral dosage form ofclaim 6, wherein the HPMC has a methoxyl content of about 19-24% and ahydroxypropyl content of about 7-12%.
 8. The controlled release oraldosage form of claim 5, wherein the high molecular weight binder has anapparent viscosity of about 80,000-120,000 cps in a 2% solution of waterat about 20° C.
 9. The controlled release oral dosage form of claim 5,wherein the high molecular weight binder has a number average weightequal to or greater than about 80,000 daltons.
 10. The controlledrelease oral dosage form of claim 5, wherein the high molecular weightbinder is HPMC, wherein the HPMC has a methoxyl content of about 19-24%and a hydroxypropyl content of about 7-12%, wherein the HPMC has anumber average weight equal to or greater than about 80,000 daltons, andwherein the HPMC has an apparent viscosity of about 80,000-120,000 cpsin a 2% solution of water at about 20° C.
 11. The controlled releaseoral dosage form of claim 5, further comprising a filler, a lubricant, aflow agent, or a combination thereof.
 12. The controlled release oraldosage form of claim 5, further comprising a filler and a lubricant. 13.The controlled release oral dosage form of claim 12, wherein the filleris lactose, and wherein the lubricant is magnesium stearate.
 14. Thecontrolled release oral dosage form of claim 12, wherein the controlledrelease oral dosage form comprises about 40% by weight of themethazolamide or pharmaceutically acceptable salt thereof, about 15% byweight of the high molecular weight binder, about 44.5% by weight of thefiller, and about 0.5% by weight of the lubricant.
 15. The controlledrelease oral dosage form of claim 1, wherein the dosage form provides anin vitro release such that 20% to 40% by weight of the methazolamide orpharmaceutically acceptable salt thereof is released at 6 hours whenmeasured by the USP Paddle Method at 100 rpm in acetate buffer (pH=4.5).16. The controlled release oral dosage form of claim 1, wherein thedosage form provides an in vitro release of from about 60% to about 70%by weight of the methazolamide or pharmaceutically acceptable saltthereof at 12 hours when measured by the USP Paddle Method at 100 rpm inacetate buffer (pH=4.5).